Mutations have recently been identified in the human tau gene that cause frontal temporal lobe dementia FTDP-17). We intend to create transgenic mice that express mutant and wild-type forms of the human tau gene. We will create several new lines carrying pathogenic mutations in a tau cDNA, and analyze these alongside a transgenic line that we have already created that over-expresses a genomic version of the normal human tau gene. These animals will be examined for basic transgene expression and will then be examined in more detail by Dr. Yen and Dickson for pathological features of the disease and abnormal tau biochemistry. We have recently developed a transgenic line of mice that over-expresses human mutant APP and PS1 (the PS/APP line) that develop very robust Alzheimer's disease related amyloidosis at approximately 12 weeks of age. The doubly transgenic animals do not however develop tau pathology in the form of paired helical filaments, or tangles. We aim to cross out genomic tau mice with the PS/APP mice to expose transgene derived human tau to the elevated beta-amyloid environment and thereby more closely mimic the situation found in the human AD brain. Triple transgenic mice will then be analyzed for AD-type changes in tau. The generation of mouse models for FTDP-17 and better models for AD will greatly enhance our resources for the study of disease etiology and may generate model systems in which to test therapeutic drugs.